Effect of Protein Kinase C β Specific Inhibition On Acute Lymphoblastic Leukemia Cell Lines.

Abstract 4817

Acute lymphoblastic leukemia (ALL) is the most common leukemia in children and accounts for 20% of acute leukemia in adults. The intensive induction–consolidation–maintenance therapeutic regimens used currently have improved the 5-year disease free survival to around 80% in children and to 25%-40% in adults. The poorer response in adults is basically due to the inability to tolerate the intensive chemotherapy, and to the biology of adult disease which is associated with poor-risk prognostic factors. In the present era of target-specific therapy, PKCβ targeting arose as a new, promising, and well tolerated treatment strategy in a variety of neoplasms, especially in B-cell malignancies. It showed encouraging results in preclinical and clinical studies involving chronic lymphocytic leukemia, diffuse large B-cell lymphoma and multiple myeloma. PKCβ plays a major role in B-cell receptor signaling, but studies describing the role of PKCβ in B-cell ALL are lacking. In the present study, we measured the sensitivity of a variety of B-cell ALL cell lines to PKCβ specific inhibition. Three cell lines were studied: RS4;11 (characterized by the t(4;11) chromosomal abnormality), TOM-1 (characterized by the t(9;22) chromosomal abnormality), and REH (characterized by the t(12;21) chromosomal abnormality). Cells were tested for PKCβ1 and PKCβ2 expression by immunoblot. Cell viability was measured when PKCβ-specific inhibitor at concentrations of 1, 2.5, 5, 10, 20 and 30 μM was added for 48 hours in the presence of 10% fetal bovine serum (FBS). MTS assay was performed to quantify cell viability. Results showed that all three cell lines express PKCβ1 and PKCβ2. Treatment with PKCβ-specific inhibitor resulted in a dose-dependent inhibition of cell proliferation; Sensitivity was evident at 1 μM for RS4;11 cell line, and at 2.5 μM for TOM-1 and REH cell lines, with 10% cell growth inhibition; Growth inhibition increased to 90% for all cell lines at an inhibitor concentration of 30 μM. These results indicate that PKCβ plays an important role in the malignant process in B-cell ALL, and suggest that PKCβ targeting should be considered as a potential treatment, whether in combination with the current regimens used or as a single agent monotherapy. Ongoing studies in our lab will detail the mechanism of PKCβ and adverse cytogenetics like t(4;11) and t(9;22).